The induction of an antigen specific T cell response requires multiple interactions between cell surface receptors on a T cell and ligands on an antigen presenting cell. The primary interaction is between the T cell receptor/CD3 complex and a major histocompatibility complex molecule, which presents an antigenic peptide to the T cell receptor, thereby triggering an antigen specific signal in the T cells. In addition to this antigen specific signal, a T cell response require a second, costimulatory signal. A costimulatory signal can be generated in a T cell by stimulation of the T cell through a cell surface receptor CD28 (Harding, F. A. (1992) Nature 356:607-609). Ligands for CD28 have been identified on antigen presenting cells (APCs). CD28 ligands include members of the B7 family of proteins, such as B7-1(CD80) and B7-2 (CD86) (Freedman, A. S. et al. (1987) J. Immunol. 137:3260-3267; Freeman, G. J. et al. (1989) J. Immunol. 143:2714-2722; Freeman, G. J. et al. (1991) J. Exp. Med. 174:625-631; Freeman, G. J. et al. (1993) Science 262:909-911; Azuma, M. et al. (1993) Nature 366:76-79; Freeman, G. J. et al. (1993) J. Exp. Med. 178:2185-2192). Additionally, B7-1 and B7-2 have been shown to bind another surface receptor on T cells related to CD28 termed CTLA4 (Linsley, P. S. (1991) J. Exp. Med. 174:561-569; Freeman, G. J. et al. (1993) Science 262:909-911). In contrast to CD28 which is constitutively expressed on T cells, CTLA4 is induced on T cells upon activation (Linsley, P. S. et al. (1992) J. Exp. Med. 176:1595-1604). Although a functional role for CTLA4 is unknown, there is some evidence that CTLA4 can synergize with CD28 in the delivery of a costimulatory signal to a T cell (Linsley, P. S. et al. (1992) J. Exp. Med. 176:1595-1604; Damle, N. K. et al. (1994) J. Immunol. 152:2686-2697).
Delivery of an antigen specific signal to a T cell in the absence of a costimulatory signal does not induce a T cell response, but rather has been found to induce a state of T cell unresponsiveness or anergy (see Schwartz, R. H. (1990) Science 248:1349; Jenkins, M. K. et al. (1988) J. Immunol. 140:3324). In a number of clinical situations it is desirable to inhibit T cell responses (e.g., in transplantation or autoimmune disorders). Thus, therapeutic approaches have been proposed to induce antigen specific T cell unresponsiveness by blocking of a costimulatory signal in T cells. For example, a CTLA4Ig fusion protein, which binds both B7-1 and B7-2, has been used to inhibit rejection of allogeneic and xenogeneic grafts (see e.g., Turka, L. A. et al. (1992) Proc. Natl. Acad. Sci. USA 89, 11102-11105; Lenschow, D. J. et al. (1992) Science 257, 789-792). Similarly, antibodies reactive with B7-1 and/or B7-2 have been used to inhibit T cell proliferation and IL-2 production in vitro and inhibit primary immune responses to antigen in vivo (Hathcock K. S. et al. (1993) Science 262, 905-907; Azuma, M. et al. (1993) Nature 366:76-79; Powers, G. D. et al. (1994) Cell. Immunol. 153, 298-311; Chen C. et al. (1994) J. Immunol. 152, 2105-2114).
An alternative approach to anergy induction for avoiding an unwanted T cell response to an antigen is to clonally delete T cells specific for the antigen, thereby eliminating the antigen specific T cells from the T cell repertoire. In vivo, T cell maturation in the thymus involves clonal deletion of potentially autoreactive T cells. Additionally, there is increasing evidence that previously activated T cells are selectively depleted in the periphery after clonal expansion and effector function has occurred (Webb, S. et al. (1990) Cell 63:1249-1256; Rocha, B. et al. (1991) Science 251:1225-1227; and Russell, J. H. et al. (1991) Proc. Natl. Acad. Sci. USA 88:2151-2155). Deletion, or elimination, of many types of cells, including T cells, can occur by a mechanism termed apoptosis, or programmed cell death. The occurrence of apoptosis in a cell is characterized by features including cell shrinkage, nuclear collapse and DNA fragmentation (reviewed in Cohen, J. J. et al. (1992) Ann. Rev. Immunol. 10:267-293). Several cell-surface molecules have been identified which, upon ligation, can induce apoptosis in a cell, including Fas and tumor necrosis factor receptors (Yonehara, S. et al. (1989) J. Exp. Med. 169:1747-1756; Trauth, B. C. et al. (1989) Science 245:301-305; Itoh, N. et al. (1991) Cell 66:233-239; and Greenblatt, M. S. et al. (1992) Blood 80:1339-1344;). However, none of these apoptotic molecules is restricted to the T cell lineage nor do they induce apoptosis in an antigen specific manner. The ability to clonally delete T cells in a manner dependent upon antigenic stimulation would provide a means for long-term inhibition of T cell responses in a variety of clinical situations without the need for chronic generalized immunosuppression of a subject with its attendant deleterious side effects.